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Background: Polymorphisms in the glutathione S-transferase pi gene ( GSTP1 ), encoding GSTP1-1, a detoxification enzyme, may increase the risk of Parkinson disease (PD) with exposure to pesticides. Using the Gene PD Study sample of familial PD cases, we explored whether GSTP1 polymorphisms were associated with the age at onset of PD symptoms and whether that relation was modified by exposure to herbicides. Methods: Seven single-nucleotide polymorphisms (SNPs) were genotyped and tested for association with PD onset age in men in three strata: no exposure to herbicides, residential exposure to herbicides, and occupational exposure to herbicides. Haplotypes were similarly evaluated in stratified analyses. Results: Three SNPs were associated with PD onset age in the group of men occupationally exposed to herbicides. Three additional SNPs had significant trends for the association of PD onset age across the herbicide exposure groups. Haplotype results also provided evidence that the relation between GSTP1 and onset age is modified by herbicide exposure. One haplotype was associated with an approximately 8-years-earlier onset in the occupationally exposed group and a 2.8-years-later onset in the nonexposed group. Conclusions: Herbicide exposure may be an effect modifier of the relation between glutathione S-transferase pi gene polymorphisms and onset age in familial PD.

Brain-derived neurotrophic factor (BDNF) stimulates neuronal growth and protects nigral dopamine neurons in animal models of Parkinson disease (PD). Therefore, BDNF is a candidate gene for PD. The authors investigated five single-nucleotide polymorphisms in 597 cases of familial PD. Homozygosity for the rare allele of the functional BDNF G196A (Val66Met) variant was associated with a 5.3-year older onset age (p = 0.0001). These findings suggest that BDNF may influence PD onset age.

We showed previously that antidepressants inhibit GABA-stimulated 36Cl- uptake in rat cerebral cortex. In this study Schild analysis was used to determine if antidepressants are competitive antagonists or allosteric modulators at GABAA receptors. GABA concentration-response curves for 36Cl- uptake in rat cerebral cortex were generated in the absence or presence of different concentrations of the following antidepressants: amitriptyline, amoxapine, mianserin, and also the GABAA receptor antagonist, bicuculline. The pA2 values for amitriptyline, amoxapine, mianserin, and bicuculline were 4.2 +/- 0.2, 5.5 +/- 0.3, 4.4 +/- 0.1 and 6.2 +/- 0.6, respectively. The respective Schild slope values were 0.7 +/- 0.1, 0.6 +/- 0.03, 0.7 +/- 0.2 and 1.0 +/- 0.3. All slope values for antidepressants differed from unity. The maximum effect produced by GABA to stimulate chloride influx was decreased by both antidepressants and bicuculline. It is concluded that neither the antidepressants studied nor bicuculline are pure competitive GABA antagonists at the GABAA receptor-chloride-ionophore complex in the rat cerebral cortex.